Understanding how drugs are eliminated from the body and how effectively they reach systemic circulation is central to biopharmaceutics. Unit 2 focuses on drug metabolism and excretion, along with the critical concepts of bioavailability and bioequivalence, which guide dose selection, formulation development, and regulatory approval of medicines. This news-style article explains these interconnected concepts in a structured and student-friendly manner.

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Drug Elimination: How the Body Removes Drugs

Drug Metabolism and Metabolic Pathways

Drug metabolism refers to the biochemical transformation of drugs into more water-soluble compounds that can be easily excreted. The liver is the primary organ of metabolism, although kidneys, lungs, intestines, and plasma enzymes also contribute.

Metabolic reactions are broadly classified into:

• Phase I reactions, including oxidation, reduction, and hydrolysis, which introduce or expose functional groups.

• Phase II reactions, such as glucuronidation, sulfation, and acetylation, which conjugate the drug or its metabolite with endogenous substances.

These pathways often reduce pharmacological activity, though some drugs form active or toxic metabolites, making metabolism a key determinant of both efficacy and safety.

Renal Excretion of Drugs

Mechanisms of Renal Drug Excretion

The kidneys play a major role in eliminating drugs and their metabolites through urine. Renal excretion occurs via three main processes:

1. Glomerular filtration, where unbound drug molecules pass freely into the filtrate.

2. Active tubular secretion, an energy-dependent process that transports drugs against concentration gradients.

3. Tubular reabsorption, where lipid-soluble drugs diffuse back into systemic circulation.

The balance between these processes determines the overall rate of drug elimination.

Factors Affecting Renal Excretion

Renal excretion is influenced by several factors, including:

• Renal blood flow and glomerular filtration rate

• Degree of plasma protein binding

• Urinary pH, which affects ionization and reabsorption

• Drug lipophilicity and molecular size

Changes in renal function due to age or disease may require dose adjustments to prevent toxicity.

Renal Clearance

Renal clearance is defined as the volume of plasma completely cleared of a drug per unit time by the kidneys. It is a quantitative measure of renal drug elimination and is crucial in determining dosing intervals and maintenance doses.

Non-Renal Routes of Drug Excretion

Alternative Excretory Pathways

Drugs may also be eliminated through bile, lungs, saliva, sweat, tears, and breast milk. Biliary excretion is particularly important for high-molecular-weight and polar compounds and may lead to enterohepatic circulation, prolonging drug action.

Pulmonary excretion is significant for volatile anesthetics, while drug excretion into breast milk has important clinical implications for lactating mothers.

Bioavailability: Measuring Drug Absorption

Definition and Objectives

Bioavailability is defined as the rate and extent to which an active drug ingredient is absorbed and becomes available at the site of action. Its primary objective is to ensure consistent therapeutic response from a dosage form.

Absolute and Relative Bioavailability

• Absolute bioavailability compares drug availability from an extravascular route to intravenous administration.

• Relative bioavailability compares two different formulations or brands of the same drug.

These measures help in formulation comparison and dosage optimization.

Measurement of Bioavailability

Pharmacokinetic Approaches

Bioavailability is commonly assessed by measuring plasma drug concentration over time. Key parameters include:

• Cmax (maximum plasma concentration)

• Tmax (time to reach Cmax)

• AUC (Area Under the Curve), representing total drug exposure

These parameters provide insight into both the rate and extent of absorption.

In-Vitro Drug Dissolution Models

Role of Dissolution Testing

In-vitro dissolution testing evaluates how quickly and completely a drug dissolves from its dosage form. Dissolution is often the rate-limiting step for absorption of poorly soluble drugs.

In-Vitro–In-Vivo Correlation (IVIVC)

IVIVC establishes a relationship between dissolution data and in-vivo bioavailability. A good IVIVC allows prediction of clinical performance based on laboratory testing, reducing the need for extensive human studies.

Bioequivalence Studies: Ensuring Therapeutic Consistency

Concept of Bioequivalence

Bioequivalence refers to the absence of a significant difference in bioavailability between two pharmaceutical products when administered at the same dose under similar conditions.

Importance in Generic Drug Approval

Bioequivalence studies ensure that generic drugs are therapeutically equivalent to branded products. Regulatory agencies require that key pharmacokinetic parameters of the test product fall within acceptable limits compared to the reference product.

Enhancing Dissolution Rate and Bioavailability

Strategies for Poorly Soluble Drugs

Poor aqueous solubility is a major challenge in drug development. Methods used to enhance dissolution and bioavailability include:

• Particle size reduction and micronization

• Solid dispersions and complexation

• Use of surfactants and co-solvents

• Lipid-based drug delivery systems

These strategies improve drug absorption and therapeutic effectiveness.